The development of a safe and reproducible gene delivery system is an essential step toward the clinical application of the hydrodynamic gene delivery (HGD) method. For this purpose, we have developed a novel electric power-driven injection system called the HydroJector-EM, which can replicate various time-pressure curves preloaded into the computer program before injection. The assessment of the reproducibility and safety of gene delivery system in vitro and in vivo demonstrated the precise replication of intravascular time-pressure curves and the reproducibility of gene delivery efficiency. The highest level of luciferase expression (272 pg luciferase per mg of proteins) was achieved safely using the time-pressure curve, which reaches 30 mm Hg in 10 s among various curves tested. Using this curve, the sustained expression of a therapeutic level of human factor IX protein (>500 ng ml(-1)) was maintained for 2 months after the HGD of the pBS-HCRHP-FIXIA plasmid. Other than a transient increase in liver enzymes that recovered in a few days, no adverse events were seen in rats. These results confirm the effectiveness of the HydroJector-EM for reproducible gene delivery and demonstrate that long-term therapeutic gene expression can be achieved by automatic computer-controlled hydrodynamic injection that can be performed by anyone.

The objective of this study is to examine the effect of hydrodynamic delivery of plasmid containing Il-15 gene on high fat diet-induced obesity and obesity-associated metabolic disorders. We demonstrate that Il-15 gene transfer results in multiple beneficial effects, including blockade of weight gain, alleviation of fatty liver and improvement in glucose homeostasis in mice. These effects are accompanied by suppressed expression of genes involved in lipogenesis and gluconeogenesis including Scd-1, Fas, Pdk4, Pepck and G6p, and enhanced expression of genes responsible for lipolysis and glucose metabolism such as Cpt1-α, Cpt1-β, Acadm, Acadl and Glut-4. Collectively, our results suggest that Il-15 gene transfer is an effective approach in preventing diet-induced obesity and obesity-associated complications.

The worldwide prevalence of obesity is increasing, raising health concerns regarding obesity-related complications. Chronic inflammation has been characterized as a major contributor to the development of obesity and obesity-associated metabolic disorders. The purpose of the current study is to assess whether overexpression of interferon beta (IFNβ1), an immune-modulating cytokine, will attenuate high fat diet-induced adipose inflammation and protect animals against obesity development. Using hydrodynamic gene transfer to elevate and sustain blood concentration of IFNβ1 in mice fed a high fat diet, we showed that overexpression of Ifnβ1 gene markedly suppressed immune cell infiltration into adipose tissue, and attenuated production of pro-inflammatory cytokines. Systemically, IFNβ1 blocked adipose tissue expansion and body weight gain, independent of food intake. Possible browning of white adipose tissue might also contribute to blockade of weight gain. More importantly, IFNβ1 improved insulin sensitivity and glucose homeostasis. These results suggest that targeting inflammation represents a practical strategy to block the development of obesity and its related pathologies. In addition, IFNβ1-based therapies have promising potential for clinical applications for the prevention and treatment of various inflammation-driven pathologies.

Obesity and its associated metabolic problems are a major public health issue. The objective of the current study is to investigate the therapeutic effects of interleukin 15/soluble interleukin 15 receptor-α (IL-15/sIL-15Rα) on high-fat diet-induced obesity and obesity-associated metabolic disorders. We demonstrate that the multiple hydrodynamic delivery of 2 μg IL-15/sIL-15Rα plasmid results in numerous beneficial effects, including a reduction of body weight and fat mass, an alleviation of fatty liver, an improvement in glucose homeostasis and insulin sensitivity in obese mice. These effects are accompanied by a suppressed expression of genes involved in lipid accumulation and lipogenesis, including Pparγ, Cd36, Fabp4, Mgat1, Scd-1 and Fas, and elevated mRNA levels of genes involved in adaptive thermogenesis and fatty acid β-oxidation, such as Ucp1, Ucp3, Pgc-1α, Pgc-1β, Pparα, Pparδ, Cpt1-α and Cpt1-β in obese animals. These results suggest that the overexpression of the Il-15/sIl-15Rα gene is an effective approach in treating diet-induced obesity and its associated metabolic complications.

Nearly 40% of people with lung cancer have tumor growth in other organs at the time of diagnosis. Current treatment strategies for patients with late-stage lung cancer are primarily palliative and only showed modest efficacy. The current study takes advantage of the hydrodynamic gene delivery technique to evaluate the antitumor activity of interleukin (IL)-15/sIL-15Rα on lung tumors growing in the lungs, liver and kidneys. We demonstrate that hydrodynamic tail vein injection of 2 μg of AG209 DP muIL-15sRα+IL-15 plasmid resulted in serum IL-15/sIL-15Rα reaching a peak level of ~10 μg ml(-1) 1 day after the injection and gradually declined to ~5 ng ml(-1) within 3 days. Quantitative PCR analysis revealed that overexpression of IL-15/sIL-15Rα induced the activation of natural killer and T cells, evidenced by increased mRNA levels of marker genes including granzyme B, perforin, Ifn-γ, T-bet and Cd8 in the lungs, liver and kidneys. Importantly, transfer of the Il-15/sIl-15Rα gene alone, or in combination with gemcitabine chemotherapy, significantly inhibited the tumor growth in these three organs and prolonged median survival time of treated mice by 1.7- and 3.3-fold, respectively. The therapeutic benefits are principally blockade and elimination of tumor growth in the liver and kidneys. Taken together, these results suggest that IL-15/sIL-15Rα-based gene therapy could be an effective approach to treat late-stage lung cancer with metastases in other organs.